OS06.7A METPlatform identifies brain metastasis vulnerabilities and predicts patient response to therapy

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii10-ii10
Author(s):  
L Zhu ◽  
C Blanco-Aparicio ◽  
L Bertero ◽  
R Soffietti ◽  
T Weiss ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Drug Screening ◽  
Human Tumor ◽  
Response To Therapy ◽  
High Morbidity ◽  
Organotypic Cultures ◽  
The Brain

Abstract BACKGROUND The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. MATERIAL AND METHODS We report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. We have applied this approach to clinically relevant stages of brain metastasis using both experimental models and human tumor tissue (by performing patient-derived organotypic cultures - PDOCs -). We have also used METPlatform to perform unbiased proteomics of brain metastases in situ to identify potential novel mediators of this disease and explore resistance mechanisms to targeted therapy. Finally, we have exploited METPlatform as “avatars” to predict response to therapy in patients with primary brain tumors. RESULTS We identified heat shock protein 90 (HSP90) as a promising therapeutic target for brain metastasis. DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis of brain metastases treated with the chaperone inhibitor revealed non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. Finally, we show that brain tumor PDOCs predict the response of the corresponding patient to standard of care, thus proving the potential of METPlatform for improving personalized care in cancer. CONCLUSION Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.

scholarly journals 42. IDENTIFICATION OF BRAIN METASTASIS VULNERABILITIES USING METPLATFORM

2020 ◽  
Vol 2 (Supplement_2) ◽  
pp. ii8-ii8
Author(s):  
Lucía Zhu ◽  
Natalia Yebra ◽  
Diana Retana ◽  
Carmen Blanco-Aparicio ◽  
Sonia Martínez ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Drug Screening ◽  
Synergistic Effects ◽  
Human Tumor ◽  
Breast Adenocarcinoma ◽  
High Morbidity ◽  
Organotypic Cultures ◽  
The Brain

Abstract The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. In this study, we report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. We have applied this approach to clinically relevant stages of brain metastasis using both experimental models and human tumor tissue (by performing patient-derived organotypic cultures). We identified heat shock protein 90 (HSP90) as a promising therapeutic target for brain metastasis. Debio-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from melanoma, lung and breast adenocarcinoma with distinct oncogenomic profiles at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, we have also used METPlatform to perform unbiased proteomics of brain metastases in situ. By applying this analysis to brain metastases treated with the chaperone inhibitor, we uncovered non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. In conclusion, our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.

scholarly journals BSCI-02. METPlatform identifies brain metastasis vulnerabilities and predicts patient response to therapy

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii1-iii1
Author(s):  
Lucía Zhu ◽  
Carmen Blanco-Aparicio ◽  
Luca Bertero ◽  
Riccardo Soffietti ◽  
Tobias Weiss ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Drug Screening ◽  
Synergistic Effects ◽  
Combined Therapy ◽  
Response To Therapy ◽  
High Morbidity ◽  
Personalized Care ◽  
The Brain

Abstract The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. We report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. By applying this approach to brain metastasis, we identified heat shock protein 90 (HSP90) as a promising therapeutic target for CNS dissemination. DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis of brain metastases treated with the chaperone inhibitor revealed non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. Finally, we have exploited METPlatform as “avatars” to show that brain tumor PDOCs predict response of the corresponding patient to standard of care, thus proving the potential of METPlatform for improving personalized care in cancer. In conclusion, our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.

scholarly journals A drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent local relapse and treat established brain metastasis

2020 ◽  
Author(s):  
Lucía Zhu ◽  
Natalia Yebra ◽  
Diana Retana ◽  
Lauritz Miarka ◽  
Elena Hernández-Encinas ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Human Brain ◽  
Drug Screening ◽  
Local Relapse ◽  
Organotypic Cultures ◽  
Systemic Spread ◽  
Screening Platform

AbstractExclusion of brain metastases from clinical trials is a major cause of the limited therapeutic options for this growing population of cancer patients. Here, we report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to brain metastasis, we identified several hits from a library of FDA approved inhibitors and others being tested in clinical trials. A blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to organotypic cultures with metastases treated with the chaperone inhibitor revealed novel biomarkers in human brain metastasis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples. We envision that METPlatform could be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.SummarySystemic spread of cancer continues to be the key aspect associated with lethality. In this publication, Zhu et al. describes a drug-screening platform specifically designed to study vulnerabilities of metastasis when colonizing secondary organs and demonstrates its value in difficult-to-treat brain metastasis using new models and patient-derived samples.

scholarly journals BSCI-11. STROMAL PLATELET DERIVED GROWTH FACTOR RECEPTOR-β (PDGFRβ) PROMOTES BREAST CANCER BRAIN METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i3-i3
Author(s):  
Katie Thies ◽  
Anisha Hammer ◽  
Blake Hildreth ◽  
Luke Russell ◽  
Steven Sizemore ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Mammary Tumor Cells ◽  
The Brain

Abstract Stromal platelet-derived growth factor receptor-beta (PDGFRβ) has emerged as an actionable mediator of breast tumor-stromal communication. As a receptor tyrosine kinase, PDGFRβ is activated by its ligand, PDGFB, which is released by neighboring tumor epithelium and endothelium. However, how PDGF signaling mediates breast cancer (BC) initiation, progression, and metastasis remains unclear. To evaluate PDGFRβ in this disease, we developed a mouse model of stromal-specific PDGFRβ activation using the Fsp-cre transgene previously published by our group. Mesenchymal-specific activation of PDGFRβ promotes preferential experimental brain metastasis of PDGFB-expressing mammary tumor cells when injected intravenously and accelerates intracranial tumor growth of these cells. Mammary tumor cells expressing low levels of PDGFB do not exhibit a similar increase in brain metastases in PDGFRβ mutant mice. To our knowledge, this is the first example where genetic manipulation of the stroma leads to an increased incidence of BCBM. Our pre-clinical data suggests that primary breast tumors that express high PDGFB could preferentially metastasize to the brain. To test this in patients, we analyzed PDGFB protein expression in a tissue microarray comprised of HER2-positive and triple negative BC primary tumors. While high PDGFB did not correlate with site-independent metastatic recurrence, it was prognostic of brain metastasis, mirroring our mouse data. Our findings suggest that high primary tumor PDGFB expression defines a subset of BC patients predisposed to brain metastases. These patients may benefit from therapeutic intervention of PDGFRβ signaling. To test this pre-clinically, we treated mice harboring intracranial tumors with the PDGFR-specific inhibitor, crenolanib. Excitingly, crenolanib treatment significantly inhibited the brain tumor burden in these mice. Combined, our findings (1) advocate that primary tumor expression of PDGFB is a novel prognostic biomarker for the development of BCBM and (2) support clinical trial evaluation of PDGFR inhibitors for the prevention and treatment of BCBM.

scholarly journals A common goal to CARE: Cancer Advocates, Researchers, and Clinicians Explore current treatments and clinical trials for breast cancer brain metastases

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Natalie S. Joe ◽  
Christine Hodgdon ◽  
Lianne Kraemer ◽  
Kristin J. Redmond ◽  
Vered Stearns ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Brain Metastases ◽  
Detection Methods ◽  
Future Research ◽  
Breast Cancer Brain Metastasis ◽  
Patient Advocates ◽  
Breast Cancer Brain Metastases ◽  
The Brain

AbstractBreast cancer is the most commonly diagnosed cancer in women worldwide. Approximately one-tenth of all patients with advanced breast cancer develop brain metastases resulting in an overall survival rate of fewer than 2 years. The challenges lie in developing new approaches to treat, monitor, and prevent breast cancer brain metastasis (BCBM). This review will provide an overview of BCBM from the integrated perspective of clinicians, researchers, and patient advocates. We will summarize the current management of BCBM, including diagnosis, treatment, and monitoring. We will highlight ongoing translational research for BCBM, including clinical trials and improved detection methods that can become the mainstay for BCBM treatment if they demonstrate efficacy. We will discuss preclinical BCBM research that focuses on the intrinsic properties of breast cancer cells and the influence of the brain microenvironment. Finally, we will spotlight emerging studies and future research needs to improve survival outcomes and preserve the quality of life for patients with BCBM.

scholarly journals Molecular and cellular mechanisms underlying brain metastasis of breast cancer

2020 ◽  
Vol 39 (3) ◽  
pp. 711-720 ◽  
Author(s):  
Mari Hosonaga ◽  
Hideyuki Saya ◽  
Yoshimi Arima
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Metastatic Cancer ◽  
Breast Cancer Patients ◽  
Cellular Mechanisms ◽  
Her2 Positive ◽  
Cells Of The Microenvironment ◽  
The Brain

Abstract Metastasis of cancer cells to the brain occurs frequently in patients with certain subtypes of breast cancer. In particular, patients with HER2-positive or triple-negative breast cancer are at high risk for the development of brain metastases. Despite recent advances in the treatment of primary breast tumors, the prognosis of breast cancer patients with brain metastases remains poor. A better understanding of the molecular and cellular mechanisms underlying brain metastasis might be expected to lead to improvements in the overall survival rate for these patients. Recent studies have revealed complex interactions between metastatic cancer cells and their microenvironment in the brain. Such interactions result in the activation of various signaling pathways related to metastasis in both cancer cells and cells of the microenvironment including astrocytes and microglia. In this review, we focus on such interactions and on their role both in the metastatic process and as potential targets for therapeutic intervention.

Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center

2014 ◽  
Vol 14 (4) ◽  
pp. 372-385 ◽  
Author(s):  
Dima Suki ◽  
Rami Khoury Abdulla ◽  
Minming Ding ◽  
Soumen Khatua ◽  
Raymond Sawaya
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Primary Tumor ◽  
Lung Metastases ◽  
Cancer Center ◽  
Leptomeningeal Disease ◽  
Tumor Type ◽  
Primary Cancer ◽  
Extracranial Metastases ◽  
The Brain

Object Metastasis to the brain is frequent in adult cancer patients but rare among children. Advances in primary tumor treatment and the associated prolonged survival are said to have increased the frequency of brain metastasis in children. The authors present a series of cases of brain metastases in children diagnosed with a solid primary cancer, evaluate brain metastasis trends, and describe tumor type, patterns of occurrence, and prognosis. Methods Patients with brain metastases whose primary cancer was diagnosed during childhood were identified in the 1990–2012 Tumor Registry at The University of Texas M.D. Anderson Cancer Center. A review of their hospital records provided demographic data, history, and clinical data, including primary cancer sites, number and location of brain metastases, sites of extracranial metastases, treatments, and outcomes. Results Fifty-four pediatric patients (1.4%) had a brain metastasis from a solid primary tumor. Sarcomas were the most common (54%), followed by melanoma (15%). The patients' median ages at diagnosis of the primary cancer and the brain metastasis were 11.37 years and 15.03 years, respectively. The primary cancer was localized at diagnosis in 48% of patients and disseminated regionally in only 14%. The primary tumor and brain metastasis presented synchronously in 15% of patients, and other extracranial metastases were present when the primary cancer was diagnosed. The remaining patients were diagnosed with brain metastasis after initiation of primary cancer treatment, with a median presentation interval of 17 months after primary cancer diagnosis (range 2–77 months). At the time of diagnosis, the brain metastasis was the first site of systemic metastasis in only 4 (8%) of the 51 patients for whom data were available. Up to 70% of patients had lung metastases when brain metastases were found. Symptoms led to the brain metastasis diagnosis in 65% of cases. Brain metastases were single in 60% of cases and multiple in 35%; 6% had only leptomeningeal disease. The median Kaplan-Meier estimates of survival after diagnoses of primary cancer and brain metastasis were 29 months (95% CI 24–34 months) and 9 months (95% CI 6–11 months), respectively. Untreated patients survived for a median of 0.9 months after brain metastasis diagnosis (95% CI 0.3–1.5 months). Those receiving treatment survived for a median of 8 months after initiation of therapy (95% CI 6–11 months). Conclusions The results of this study challenge the current notion of an increased incidence of brain metastases among children with a solid primary cancer. The earlier diagnosis of the primary cancer, prior to its dissemination to distant sites (especially the brain), and initiation of presumably more effective treatments may support such an observation. However, although the actual number of cases may not be increasing, the prognosis after the diagnosis of a brain metastasis remains poor regardless of the management strategy.

scholarly journals Brain Metastases in Soft Tissue Sarcomas: Case Report and Literature Review

Sarcoma ◽  
2005 ◽  
Vol 9 (3-4) ◽  
pp. 147-150 ◽  
Author(s):  
Tejpal Gupta ◽  
Siddhartha Laskar ◽  
Sumeet Gujral ◽  
Mary Ann Muckaden
Keyword(s):  
Soft Tissue ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Soft Tissue Sarcomas ◽  
Whole Brain Radiotherapy ◽  
Palliative Radiotherapy ◽  
Adolescent Male ◽  
Spindle Cell Sarcoma ◽  
Solitary Brain Metastasis ◽  
The Brain

Background and purpose:Brain metastasis is a relatively uncommon event in the natural history of soft tissue sarcomas. The increasing use of chemotherapy may have caused a reduction in local relapses as well as distant failures leading to an improvement in survival, thereby allowing metachronous seeding of the brain, a sanctuary site. The purpose of this report is to increase awareness amongst clinicians regarding such a possibility.Patients and methods:A review of the departmental sarcoma database following the presentation of this index case in the clinic.Results and discussion:An adolescent male who had previously been treated with surgery and radiotherapy for a spindle cell sarcoma of the left thigh developed a space-occupying lesion in the brain within 6 months of treatment of the primary tumor. He subsequently underwent resection of the presumed solitary brain metastasis followed by whole brain radiotherapy. On radiation he was detected to have pulmonary metastases too, for which he was offered palliative chemotherapy. The patient died of brain metastasis within 4 months. A review of the departmental sarcoma database, restricted to soft tissue sarcomas purely, maintained prospectively from 2000 till date, could not identify any other such case.Conclusion:Brain metastases from soft tissue sarcomas are rare. Patients with neurological symptoms, however, should be appropriately investigated. Surgical resection of brain metastasis could be considered for solitary brain metastasis in non-eloquent areas. Palliative radiotherapy is appropriate for patients with multiple brain metastases or co-existing extra-cranial disease.

Metastatic Liposarcoma of the Brain with Response to Chemotherapy: Case Report

Neurosurgery ◽  
1988 ◽  
Vol 23 (6) ◽  
pp. 777-780 ◽  
Author(s):  
Harold Haft ◽  
George C. Wang
Keyword(s):  
Case Report ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Abdominal Mass ◽  
Response To Chemotherapy ◽  
History Of ◽  
In The Beginning ◽  
The Brain

Abstract Metastatic liposarcomas to the brain are rare. The authors describe a patient with a 20-year history of liposarcoma originating in the thigh and metastatic to the brain 18 years later. The brain metastasis was removed by surgery. Nine months later, the patient developed metastases to the retroperitoneum and liver. At that same time, she had recurrent brain metastasis. She was then treated with chemotherapy. The abdominal mass shrank considerably in the beginning, and the recurrent brain metastases totally disappeared. The patient eventually succumbed to widespread liposarcoma. Autopsy revealed extensive liposarcoma involving the retroperitoneum, liver, and lung, but no trace of tumor was found in the brain.

scholarly journals Gene Expression Profile in Primary Tumor Is Associated with Brain-Tropism of Metastasis from Lung Adenocarcinoma

2021 ◽  
Vol 22 (24) ◽  
pp. 13374
Author(s):  
Yen-Yu Lin ◽  
Yu-Chao Wang ◽  
Da-Wei Yeh ◽  
Chen-Yu Hung ◽  
Yi-Chen Yeh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Dna Sequencing ◽  
Lung Adenocarcinoma ◽  
Rna Sequencing ◽  
Cell Lines ◽  
Differentially Expressed Genes ◽  
Primary Tumor ◽  
The Brain

Lung adenocarcinoma has a strong propensity to metastasize to the brain. The brain metastases are difficult to treat and can cause significant morbidity and mortality. Identifying patients with increased risk of developing brain metastasis can assist medical decision-making, facilitating a closer surveillance or justifying a preventive treatment. We analyzed 27 lung adenocarcinoma patients who received a primary lung tumor resection and developed metastases within 5 years after the surgery. Among these patients, 16 developed brain metastases and 11 developed non-brain metastases only. We performed targeted DNA sequencing, RNA sequencing and immunohistochemistry to characterize the difference between the primary tumors. We also compared our findings to the published data of brain-tropic and non-brain-tropic lung adenocarcinoma cell lines. The results demonstrated that the targeted tumor DNA sequencing did not reveal a significant difference between the groups, but the RNA sequencing identified 390 differentially expressed genes. A gene expression signature including CDKN2A could identify 100% of brain-metastasizing tumors with a 91% specificity. However, when compared to the differentially expressed genes between brain-tropic and non-brain-tropic lung cancer cell lines, a different set of genes was shared between the patient data and the cell line data, which include many genes implicated in the cancer-glia/neuron interaction. Our findings indicate that it is possible to identify lung adenocarcinoma patients at the highest risk for brain metastasis by analyzing the primary tumor. Further investigation is required to elucidate the mechanism behind these associations and to identify potential treatment targets.

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